A number of important human diseases, including rheumatoid arthritis (RA), insulin dependent diabetes mellitus (IDDM), multiple sclerosis (MS), myasthenia gravis (MG) and others, are associated with polymorphisms of major histocompatibility complex class II molecules. This suggests that highly specific immunological interventions directed at these polymorphisms may be an effective therapeutic strategy, replacing the nonspecific, chronic immunosuppression which is a mainstay of current therapy. A potential candidate intervention is the use of synthetic peptides which block the binding of disease-inducing antigens to the relevant MHC class II polymorphic structures, preventing the activation of autoimmune T lymphocytes. Recent success in preventing experimental autoimmune encephalitis, a mouse model of MS, provides an outline for the current study. This proposal will study experimental autoimmune myasthenia gravis (EAMG), induced in susceptible C57BL/6 (B6) mice by immunization with acetylcholine receptor (AChR). EAMG is both immunologically and pathophysiologically more complex than EAE and should provide a challenging test of the general applicability of the peptide strategy. B6 mice will be immunized with AChR and cloned AChR-reactive T cell lines established. The T cell recognition sites of AChR will be precisely defined by using synthetic peptides representing AChR sequences. Peptide residues recognized by T cells (epitopes) and residues which mediate binding to MHC class II molecules (agretopes) will be defined. Substituted peptides which possess AChR agretope residues but not epitope residues contained within the immunodominant T cell sites should be capable of preventing the activation of T cell clones in vitro, lymph node T cells ex vivo and EAMG induction in vivo. The project uses standard methology, but brings together the expertise of three key collaborators: AJI - T cell clones, KAW - peptide synthesis and KAK- EAMG model.